Malaria is a devastating disease that affects over one billion people and causes approximately 1 million deaths annually. Although there are a number of drugs used to treat the disease, resistance to these drugs is becoming more widespread. Superior long-term solutions for combatting resistant parasites require identification of novel antimalarial drug targets and compound classes that kill the parasite with unique mechanisms of action. Plasmodium falciparum, the most deadly species to humans, as well as other malaria- causing species of Plasmodium, have multiple aspartic proteases that are essential to the parasite's survival. We propose to (1) optimize the antimalarial activity of two classes of asparti protease inhibitors and (2) determine their unique mechanism of action as antimalarial agents. Through our preliminary collaborative efforts, we have already identified drug-like aspartic protease inhibitors with inherent antimalarial activity and oral efficacy for suitable optimizationas drugs. In order to efficiently address the critical need for novel antimalarials, the Center for World Health & Medicine (CWHM) at Saint Louis University has established a research collaboration with the Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences. CWHM is a non-profit institute comprised of highly skilled and successful former Pfizer drug discovery scientists with expertise in the translation of basic science into the discovery and development of novel drugs for challenging targets. GIBH is a leading Chinese center of expertise in malaria biology, drug discovery and medicinal chemistry. This unique collaboration encompasses the expertise and resources necessary to successfully demonstrate the viability of novel aspartic protease inhibitors as antimalarial agents and to determine of thei mechanism(s) of action for target-based drug discovery.